Physician's management of suspected vitamin B12 deficiency

A retrospective study was undertaken to audit physician's management of patients with a low serum level of vitamin B12 who were admitted to a university-affiliated teaching hospital during 1 year. Among the 34 patients 13 were proved to have pernicious anemia or vitamin B12 malabsorption, but for 12 of them there were unnecessary delays (several days or weeks) before initiation of investigation and therapy. An additional six patients, who had low serum levels of vitamin B12 and macrocytosis, most likely had true vitamin B12 deficiency, but proper investigation was not done and they did not receive any vitamin B12 or folic acid therapy. In another nine cases unexplained low serum levels of vitamin B12 were not properly investigated, and the patients either did not receive any vitamin B12 therapy or received it without proper documentation of a deficiency. Suggestions for facilitating early detection, investigation and treatment of megaloblastic anemia or vitamin B12 deficiency are given.     

Anaemia, macrocytosis, vitamin B12 and folate levels in elderly Zimbabweans

OBJECTIVES: To establish the ranges of full blood count (FBC), vitamin B12 and folate levels and to determine the prevalence of occult haematological abnormalities in older Zimbabweans. STUDY DESIGN: Community based cross sectional survey. SUBJECTS: 278 randomly selected healthy Zimbabweans aged > 65 years. INTERVENTIONS/STUDY FACTORS: Haemoglobin level, MCV, folate, B12 alcohol consumption. RESULTS: The median Hb was males 14.0 (range 8 to 18.3), females 13.1 g/dl (7.9 to 18.1). 23% were anaemic (Hb < 13 g/dl in males, < 12 g/dl in females), 3% with microcytic and 20% with macrocytic indices. Overall 13% had low vitamin B12 and 30% had low folate levels. Folate levels were significantly lower in urban subjects and B12 levels were significantly lower in rural subjects. Fifty four subjects (21%) had an MCV > 100 fl. In this group, low folate levels were found in 22, low B12 levels in nine, excessive alcohol in eight and two subjects had elevated TSH. The MCV was higher in urban subjects. CONCLUSIONS: This study has revealed a large amount of occult haematological abnormality and interesting differences between rural and urban subjects. It focuses attention on low levels of folate, which should be preventable by simple nutritional education, as an extensive problem in the community.     

The end of the cob operon: evidence that the last gene (cobT) catalyzes synthesis of the lower ligand of vitamin B12, dimethylbenzimidazole

The cob operon of Salmonella typhimurium includes 20 genes devoted to the synthesis of adenosyl-cobalamin (coenzyme B12). Mutants with lesions in the promoter-distal end of the operon synthesize vitamin B12 only if provided with 5,6-dimethylbenzimidazole (DMB), the lower ligand of vitamin B12. In the hope of identifying a gene(s) involved in synthesis of DMB, the DNA base sequence of the end of the operon has been determined; this completes the sequence of the cob operon. The cobT gene is the last gene in the operon. Four CobII (DMB-) mutations mapping to different deletion intervals of the CobII region were sequenced; all affect the cobT open reading frame. Both the CobT protein of S. typhimurium and its Pseudomonas homolog have been shown in vitro to catalyze the transfer of ribose phosphate from nicotinate mononucleotide to DMB. This reaction does not contribute to DMB synthesis but rather is the first step in joining DMB to the corrin ring compound cobinamide. Thus, the phenotype of Salmonella cobT mutants conflicts with the reported activity of the affected enzyme, while Pseudomonas mutants have the expected phenotype. J. R. Trzebiatowski, G. A. O'Toole, and J. C. Escalante Semerena have suggested (J. Bacteriol. 176:3568-3575, 1994) that S. typhimurium possesses a second phosphoribosyltransferase activity (CobB) that requires a high concentration of DMB for its activity. We support that suggestion and, in addition, provide evidence that the CobT protein catalyzes both the synthesis of DMB and transfer of ribose phosphate. Some cobT mutants appear defective only in DMB synthesis, since they grow on low levels of DMB and retain their CobII phenotype in the presence of a cobB mutation. Other mutants including those with deletions, appear defective in transferase, since they require a high level of DMB (to activate CobB) and, in combination with a cobB mutation, they eliminate the ability to join DMB and cobinamide. Immediately downstream of the cob operon is a gene (called ORF in this study) of unknown function whose mutants have no detected phenotype. Just counterclockwise of ORF is an asparagine tRNA gene (probably asnU). Farther counterclockwise, a serine tRNA gene (serU or supD) is weakly cotransducible with the cobT gene.     

The effect of vitamin B12 deficiency on older veterans and its relationship to health

OBJECTIVE: To examine the effect of vitamin B12 deficiency on older veterans and its relationship to general health and cognitive impairment. DESIGN: Cross-sectional study. SETTING: Oklahoma City Veterans Affairs Medical Center. PARTICIPANTS: Data for this research were obtained from 303 ambulatory, older veterans who used the outpatient laboratories of the Oklahoma City Department of Veterans Affairs Medical Center. Subjects were included in the study if they were 65 years of age and older and if they had no known diagnosis associated with B12 deficiency. The sample in this study consisted of 301 men and 2 women aged 65 to 89 years. MEASUREMENTS: This study used two separate measurements of vitamin B12 deficiency: (1) a strict definition of B12 deficiency (serum B12 level < laboratory norm) and (2) a broader definition of B12 deficiency (serum B12 level < laboratory norm or laboratory norm < B12 < 300 pg/mL and methyl malonic acid (MMA) or homocysteine (HC) elevated by more than two standard deviations). The laboratory norm is 200 pg/mL. The dependent variables were measures of cognitive impairment and general health. Cognitive impairment was measured using the Folstein Mini-Mental State Examination (MMSE) and general health was measured using the RAND 36-Item Health Survey Version 1.0. The control variables for this study were the subjects' daily alcohol intake, daily intake of a vitamin/mineral supplement, annual income, and level of education. RESULTS/CONCLUSIONS: Nineteen subjects (6%) were vitamin B12-deficient as measured by the strict definition of B12 deficiency (serum B12 level < laboratory norm), and 49 subjects (16%) were vitamin B12-deficient as measured by the broader definition of B12 deficiency (serum B12 level < laboratory norm or laboratory norm < B12 < 300 pg/mL and MMA or HC elevated by more than two standard deviations). Vitamin B12 level decreases as age increases. Of the nine general health outcomes measured by using the RAND 36-Item Health Survey, only bodily pain is associated with vitamin B12 deficiency, and only then when B12 deficiency is measured as serum B12 level < laboratory norm, the strict definition of B12 deficiency. Vitamin B12-deficient subjects experience more bodily pain than those with normal vitamin B12 levels. There is a significant difference between B12-deficient subjects and B12 normal subjects on cognitive impairment, with B12 normal subjects indicating less cognitive impairment, only when B12 deficiency is measured as B12 level < laboratory norm, the strict definition of B12 deficiency. The broader measurement of vitamin B12 deficiency (i.e., serum B12 level < laboratory norm or laboratory norm < B12 < 300 pg/mL and MMA or HC elevated by more than two standard deviations) is not a significant correlate of cognitive impairment and general health.     

Intestinal absorption of vitamin B12 in patients with chronic pancreatic insufficiency and the effect of human duodenal juice on the intestinal uptake of vitamin B12

The mean absorption of vitamin B12 (Schilling test) was 13.1 +/- 1.0 (% +/- S.E.M.) in 21 patients with chronic pancreatic insufficiency and 17.6 +/- 1.4 in 13 control patients (p less than 0.01). There was no correlation between pancreatic bicarbonate production after secretion stimulation and vitamin B12 absorption in the patient group (r = 0.117). Human duodenal juice reduced the uptake of 57CoB12-rat intrinsic factor (IF) by perfused rat small intestinal segments in vivo (p less than 0.01) as well as the uptake of 57CoB12-human IF by purified guinea-pig intestinal brush borders in vitro (p less than 0.01). The results confirm reduced absorption of vitamin B12 in chronic pancreatic insufficiency, but the mechanism remains uncertain.     

Electrochemical Behavior of Bulk Amorphous Steel Fe55M2Cr12Mo10B5C13Y2(M=Ni,Cu,Nb)

Fe55Ni2Cr12Mo10B6C13Y2,Fe55Cu2Cr12Mo10B6C13Y2 and Fe55Nb2Cr12Mo10B6C13Y2 alloys with diameter of 4 mm were produced by copper mold casting. The effect of alloying additions (Ni,Cu or Nb) on corrosion resistance of Fe55 Ni2 Cr2Mo10 B6 C13 Y2,Fe55Ni2Cr12Mo10B6C13Y2 and Fe55 Cu2 Cr12 Mo10 B6 C13 Y2 alloys was studied by polarization curves and electrochemical impedance spectroscopy (EIS). The results show that Fe55Ni2Cr12Mo10B6C13 Y2 and Fe55Cu2Cr12Mo10B6C13 Y2 alloys can be cast to form bulk metallic glasses. Fe55Ni2Cr12Mo10B6C13 Y2 and Fe55Cu2Cr12 Mo10B6C13Y2 amorphous alloys with passive potential about 1500 mV exhibit good corrosion resistance in NaCl solution of 5 % and 1 mol/L HC1 solution. The passive current density of the alloy with Ni addition is lower than that of other alloys. EIS results only show one impedance element. Amorphous alloy Fe55 Ni2 Cr12 Mo10 B6 C13 Y2 with larger charge transfer reaction resistance indicates good corrosion resistance.     

The cytotoxic effect of the vitamin B12 inhibitor cyanocobalamin [c-lactam], and a review of other vitamin B12 antagonists

The vitamin B12 antagonist cyanocobalamin [c-lactam] was cytotoxic to cultured human leukemia cells, grown in methylfolate, homocysteine, and vitamin B12, but not in the presence of methionine. Small concentrations of methionine were effective in restoring the growth rate in a dose-dependent fashion, confirming methionine deficiency as the cytotoxic principle. Cyanocobalamin [c-lactam] prevented utilization of the methyl group of methylfolate, but no evidence of folate deficiency developed in long-term culture. High concentrations of non-methylated folate were unable to reverse the cytotoxicity, excluding a methylfolate 'trap' as the cause. Low concentrations of serine in the medium induced transient biochemical megaloblastosis. Cyanocobalamin [c-lactam] caused this to occur earlier, and persist. In high concentrations of serine, the inhibitor caused only transient changes in deoxyuridine suppression. Homocysteine cannot be remethylated without vitamin B12, and condensation with serine is the only other excretory pathway for this toxic amino acid. We hypothesize that impaired DNA synthesis in vitamin B12 deficiency is the result of diverting serine away from thymidylate synthesis, into homocysteine metabolism.     

Ischemic strokes secondary to vitamin B12 deficiency-induced hyperhomocystinemia

A 45-year-old woman sustained two ischemic cerebral infarctions 16 years after ileal resection for Crohn's disease. Her evaluation showed an elevated random serum homocystine level, a low serum vitamin B12 level, and an increased mean corpuscular volume (MCV) without anemia. A methionine-loading test resulted in a marked increase in the homocystine levels 2, 4, and 6 hours after the load. A Schilling test demonstrated a malabsorption of vitamin B12. Vitamin B12 injections normalized her fasting homocystine level and her MCV. She has had no recurrent strokes during a year follow-up.     

Effects of B vitamin injections on plasma B vitamin concentrations of feed-restricted beef calves infected with bovine herpesvirus-1

For nonruminants, stress and disease greatly increase requirements for vitamin B6, folic acid, pantothenic acid, and ascorbate. The effects of feed restriction, virus infection, and vitamin injections on plasma concentrations of B vitamins critical to the immune response were evaluated. Twelve beef steer calves, 6 to 8 mo of age, were fed below maintenance for 17 d and deprived of food for 3 d during a 20-d period after weaning. They then were inoculated intranasally with live attenuated bovine herpesvirus-1 (BHV-1). Six calves received saline injections and six received injections of a B vitamin mixture and ascorbate every 48 h for 14 d before and 14 d after inoculation. A mild respiratory infection developed in all calves 4 to 5 d after inoculation. In control calves, restricted intake and food deprivation decreased plasma vitamin B6 and pantothenate and increased vitamin B12 but did not affect folic acid and ascorbate concentrations. Vitamin injections increased plasma concentrations of vitamin B6, folic acid, vitamin B12, pantothenic acid, and ascorbate (P < .002). Plasma concentrations of vitamin B6, vitamin B12, pantothenic acid, and ascorbate, but not folic acid, were markedly reduced in all calves during the BHV-1 infection (P = .001). The vitamin B6, pantothenic acid, vitamin B12, and ascorbate status of stressed calves may affect their immune response to vaccination or infection.     

The biogenetic anatomy of vitamin B6. A 13C NMR investigation of the biosynthesis of pyridoxol in Escherichia coli

It is shown by incorporation experiments with 13C bond-labeled substrates, followed by analysis by means of 13C NMR spectroscopy, that two compounds, 1-deoxy-D-xylulose (12) and 4-hydroxy-L-threonine (), serve as precursors of pyridoxol (vitamin B6) (1) in Escherichia coli. Together, these two compounds account for the entire C8N skeleton of the vitamin. 1-Deoxy-D-xylulose supplies the intact C5 unit, C-2',2,3,4,4' of pyridoxol. 4-Hydroxy-L-threonine undergoes decarboxylation in supplying the intact C3N unit, N-1,C-6,5,5'. Both precursors are ultimately derived from glucose. The C5 unit of pyridoxol that is derived from 1-deoxy-D-xylulose originates by union of a triose phosphate (yielding C-3,4,4') with pyruvic acid (which decarboxylates to yield C-2',2). D-Erythroate (11) enters the C3 unit, C-6,5,5', and is therefore an intermediate on the route from glucose into 4-hydroxy-L-threonine.     

Cigarette smoking, serum lipids, folate, and vitamin B12 in lung cancer

The purpose of our study was to evaluate the effects of cigarette smoking and serum lipids, folate, and vitamin B12 on the development of lung cancer in the Turkish population. The study group consisted of patients with histologically proven lung cancer and the control group comprised healthy smokers being followed in our smoking cessation outpatient department. Smoking history was obtained from all subjects and serum total cholesterol, HDL cholesterol, triglycerides, vitamin B12, and folate levels were measured. Pack/years of cigarettes smoked were significantly higher in the subjects with lung cancer than in the control group (p < 0.01). Serum total cholesterol, HDL cholesterol, triglyceride, serum folate, and vitamin B12 levels were within normal limits in both groups (p < 0.05), but serum vitamin B12 levels were statistically significantly higher (p < 0.01) in the cancer group than in the controls. In our study, we did not observe low levels of serum cholesterol, vitamin B12, or folate in the lung cancer patients.     

Megaloblastic anaemia in childhood due to vitamin B12 deficiency, report of 3 cases of congenital selective vitamin B12 malabsorption (author''s tranls)

Three cases of congenital selective malabsorption of vitamin B12 (Imerslund-Grasbeck syndrome) are presented. Pathophysiological aspected and clinical symptoms of this disease are discussed together with other megaloblastic anaemias in childhood caused by vitamin B12 deficiency.     

Electrochemical Behavior of Bulk Amorphous Steel Fe55M2Cr12Mo10B6C13Y2（M=Ni, Cu, Nb）

 Fe55Ni2Cr12Mo10B6C13Y2,Fe55Cu2Cr12Mo10B6C13Y2 and Fe55Nb2Cr12Mo10B6C13Y2 alloys with diameter of 4mm were produced by copper mold casting. The role of alloying additions (Ni, Cu or Nb) on corrosion resistance of Fe55Nb2Cr12Mo10B6C13Y2, Fe55Ni2Cr12Mo10B6C13Y2 and Fe55Cu2Cr12Mo10B6C13Y2 alloys were studied by polarization curves and electrochemical impedance spectroscopy (EIS). The results show that Fe55Ni2Cr12Mo10B6C13Y2 and Fe55Cu2Cr12Mo10B6C13Y2 alloys can be cast into bulk metallic glasses. Fe55Ni2Cr12Mo10B6C13Y2 and     

Influence of vitamin B6 intake on the content of the vitamin in human milk

The influence of the level of vitamin B6 intake on the content of the vitamin in milk was studied in 19 healthy subjects whose stages of lactation ranged from 3 weeks to 30 months. Total vitamin B6 intakes, including extra-dietary sources of the vitamin, ranged from 1.3 to 12.5 mg per day with six subjects consuming less than the recommended allowance of 2.5 mg per day (RDA, 1974). Subjects consuming less than 2.5 mg of vitamin B6 per day had significantly less vitamin B6/liter milk (129 mug) than groups consuming 2.5 to 5.0 or greater than 5.0 mg per day (239 and 314 mug, respectively). Among subjects consuming greater than 2.5 mg of vitamin per day the stage of lactation did not influence the levels of protein or vitamin B6 in milk. Vitamin B6 intakes two to five times the recommended allowance did not significantly elevate the level of the vitamin in milk compared to values for subjects whose intakes approximated the allowance. The vitamin B6/protein ratio in milk of subjects consuming less than 2.5 mg vitamin B6 per day was 13 mug/g and was significantly lower than that observed for the other two groups (23 and 28 mug/g). Daily and weekly variations of the vitamin B6 and protein content in milk of individuals were small. However, marked diurnal variations in the vitamin B6 content were found in milk of individuals taking daily supplements of the vitamin with peak levels occurring in the afternoon 3 to 5 hr after supplements were taken in the morning.     

Radioisotopic assay of vitamin B12 in tissues

The present study delineates the application of the radioisotopic competitive-inhibition assay for the measurement of vitamin B12 in tissues. The extraction of endogenous B12 from tissues was shown to be simple and complete. Proportional dilution studies suggest that tissue factors do not interfere with the assay. Although some variability exists when multiple areas of an organ are sampled, the differences between B12 levels in tissues obtained from normal individuals and B12-deprived individuals are so wide that individual intra-organ variability is trivial, As this tissue B12 assay is similar to the widely utilized radioisotopic assays for serum B12, it is applicable for routine use.     

Demonstration of vitamin B12 analogues in human sera not detected by microbiological assay

Sera were absorbed with polyacrylamide beads to which purified human intrinsic factor was attached. This procedure removed the vitamin B12 analogues which are measured by microbiological assay with Lactobacillus leichmannii and Euglena gracilis and which are measured in an isotope dilution method using intrinsic factor. Such sera still contained B12 analogues that were assayed in an isotope dilution method using a non-intrinsic factor vitamin B12 binder. Such vitamin B12 analogues make up approximately half of the total vitamin B12 analogues in human serum.     

Peritoneal clearance and peritoneal transfer of oxalic acid, vitamin C, and vitamin B6 during continuous ambulatory peritoneal dialysis

The peritoneal clearance and peritoneal transfer of oxalic acid, vitamin C, and vitamin B6 in 32 patients during continuous ambulatory peritoneal dialysis (CAPD) using peritoneal dialysis solutions containing 1.5% or 2.5% glucose were examined. The plasma level of oxalic acid was significantly elevated in all patients, plasma vitamin C was in the normal range or in the upper margin of the normal range, and plasma vitamin B6 was in the normal range. The peritoneal clearance of oxalic acid was significantly lower, and the peritoneal clearance of vitamin B6 was the lowest in comparison to the peritoneal clearance of urea. With the exception of vitamin B6, the peritoneal clearance and peritoneal transfer of the examined parameters increased using the dialysis solution containing 2.5% glucose. We found direct relationships between the plasma levels of oxalic acid and creatinine as well as plasma vitamin C and between the peritoneal transfer of oxalic acid and the peritoneal transfer of vitamin C as well as vitamin B6. The significant hyperoxalemia of our patients was found to persist despite the relatively high peritoneal transfer of oxalic acid during CAPD. These results suggest that CAPD is not a method effective enough for permanent reduction of the plasma levels of oxalic acid.     

Inhibitory effect of eggs on vitamin B12 absorption: description of a simple ovalbumin 57Co-vitamin B12 absorption test

Ovalbumin and egg yolks, mixed separately in vitro with radiocyanocobalamin (57 Co-vitamin B12), were served to normal volunteers in a cooked form. Ovalbumin, and to a lesser degree, egg yolks were observed to inhibit vitamin B12 absorption. This observation explains the rather poor assimilation of vitamin B12 from eggs labelled in vivo with 57 Co-vitamin B12.     

Correction of the DNA synthesis defect in vitamin B12 deficiency by tetrahydrofolate: evidence in favour of the methyl-folate trap hypothesis as the cause of megaloblastic anaemia in vitamin B12 deficiency

The critical disturbance of folate metabolism caused by vitamin B12 deficiency which results in megaloblastic anaemia remains controversial. Vitamin B12 is required in the methionine synthase reaction in which homocysteine is converted to methionine and methyl tetrahydrofolate (methyl THF) to THF. The 'methyl-folate trap' hypothesis suggested that failure of demethylation of methyl THF with consequent deficiency of folate co-enzymes derived from THF is the crucial lesion caused by vitamin B12 deficiency. A more recent theory suggested that reduced supply of methionine leads to reduced availability of 'activated formate' and hence of formyl THF and it is this defect that results in failure of folate co-enzyme synthesis. The present results, based on deoxyuridine suppression tests on 103 cases of megaloblastic anaemia, show that THF itself is equally capable of correcting the failure of thymidylate synthesis in vitamin B12 deficiency as in folate deficiency. Although not as effective as formyl THF in correcting the dU blocking test in vitamin B12 deficiency, this is equally so for the correction of the test by THF compared with formyl THF in folate deficiency. The results therefore favour the theory that it is in the supply of THF and not of 'active formate' or formyl THF that vitamin B12 plays a critical role in folate metabolism.     

Folate, vitamin B12, and serum total homocysteine levels in confirmed Alzheimer disease

BACKGROUND: Recent studies suggest that vascular disease may contribute to the cause of Alzheimer disease (AD). Since elevated plasma total homocysteine (tHcy) level is a risk factor for vascular disease, it may also be relevant to AD. OBJECTIVE: To examine the association of AD with blood levels of tHcy, and its biological determinants folate and vitamin B12. DESIGN: Case-control study of 164 patients, aged 55 years or older, with a clinical diagnosis of dementia of Alzheimer type (DAT), including 76 patients with histologically confirmed AD and 108 control subjects. SETTING: Referral population to a hospital clinic between July 1988 and April 1996. MAIN OUTCOME MEASURES: Serum tHcy, folate, and vitamin B12 levels in patients and controls at entry; the odds ratio of DAT or confirmed AD with elevated tHcy or low vitamin levels; and the rate of disease progression in relation to tHcy levels at entry. RESULTS: Serum tHcy levels were significantly higher and serum folate and vitamin B12 levels were lower in patients with DAT and patients with histologically confirmed AD than in controls. The odds ratio of confirmed AD associated with a tHcy level in the top third (> or = 14 micromol/L) compared with the bottom third (< or = 11 micromol/L) of the control distribution was 4.5 (95% confidence interval, 2.2-9.2), after adjustment for age, sex, social class, cigarette smoking, and apolipoprotein E epsilon4. The corresponding odds ratio for the lower third compared with the upper third of serum folate distribution was 3.3 (95% confidence interval, 1.8-6.3) and of vitamin B12 distribution was 4.3 (95% confidence interval, 2.1-8.8). The mean tHcy levels were unaltered by duration of symptoms before enrollment and were stable for several years afterward. In a 3-year follow-up of patients with DAT, radiological evidence of disease progression was greater among those with higher tHcy levels at entry. CONCLUSIONS: Low blood levels of folate and vitamin B12, and elevated tHcy levels were associated with AD. The stability of tHcy levels over time and lack of relationship with duration of symptoms argue against these findings being a consequence of disease and warrant further studies to assess the clinical relevance of these associations for AD.